The first antibody response to transmitted/founder HIV-1 envelope is non-neutralizing, targets Env gp41 and occurs at a mean of 13 days after appearance of plasma viremia (Tomaras et al, J. Virology 82:12449-63 (2008)). While the initial T cell response to HIV-1 that occurs at the same time as the initial antibody response drives mutations within T cell epitopes of HIV-1, the initial gp41 antibody response to HIV-1 does not. Rather, it is the autologous neutralizing antibody response, which is delayed until approximately three months after transmission, that is the first neutralizing antibody response associated with antibody escape mutants (McMichael et al, Nature Rev. Immunol. 10:11-23 (2010)).
The four epitopes on HIV-1 envelope to which rare broadly reactive neutralizing antibodies bind are the CD4 binding site (CD4BS) (mab (monoclonal antibody) IgG1b12) (Zwick et al, J. Virol. 77(10):5863-5876 (2003)), the membrane proximal external region (MPER) epitopes defined by human mabs 2F5 and 4E10 (Armbruster et al, J. Antimicrob. Chemother. 54:915-920 (2004), Stiegler and Katinger, J. Antimicrob. Chemother. 51:757-759 (2003), Zwick et al, Journal of Virology 79:1252-1261 (2005), Purtscher et al, AIDS 10:587 (1996)), and the mannan glycan epitope defined by human mab 2G12 (Scanlan et al, Adv. Exper. Med. Biol. 535:205-218 (2003)). These four rare human mabs are all unusual: two are IgG3 (2F5 and 4E10), one has a unique Ig dimer structure (2G12), one has a very hydrophobic CDR3 (2F5) (Ofek et al, J. Virol. 198:10724 (2004)), and, in all four, the CDR3 is unusually long (Burton et al, Nature Immunol. 5(3):233-236 (2004), Kunert et al, AIDS Res. Hum. Retroviruses 20(7):755-762 (2004), Zwick et al, J. Virol. 78(6):3155-3161 (2004), Cardoso et al, Immunity 22:163-172 (2005)). Of these, 2F5- and 4E10-like human mabs are quite rare. Acute HIV-1 patients do not make antibodies against the MPER or 2G12 epitopes, MPER can be defined as amino acids 652 to 683 of HIV envelope (Cardoso et al, Immunity 22:163-173 (2005) (e.g., QQEKNEQELLELDKWASLWNWFDITNWLWYIK) (SEQ ID NO: 1). CD4 binding site (BS) antibodies are commonly made early in HIV-1 infection, but these antibodies generally do not have the broad spectrum of neutralization shown by mab IgG1b12 (Burton et al, Nat. Immunol. 5(3):233-236 (2004)).
To understand the pathogenesis of the ineffective initial antibody response to HIV-1 envelope (Env), PCR has been performed for amplification of immunoglobulin variable region of heavy- and light-chain (VH and VL) genes from single blood or bone marrow plasma cells from 5 acutely infected subjects from 17-30 days after HIV-1 transmission. The specificities of the plasma cell response induced by HIV-1 infection have been determined. Using PCR amplification of VH and VL genes of single human plasma cells induced by transmitted HIV-1, the initial plasma cell/plasmablast response to HIV-1 has been studied. It has been found that the first antibody response to HIV-1 is induced to HIV-1 Env gp41, and that gp41 induces an antibody response in pre-existing memory B cell clones, resulting in low-affinity, polyreactive anti-Env antibodies that cross-react with a number of host and bacterial molecules, particularly, of human gut bacterial flora.
The present invention results, at least in part, from studies designed to identify the source of both the initial anti-HIV-1 Env gp41 antibodies and the rare broadly neutralizing antibodies. The invention further results from the identification of a cellular protein expressed in most warm blooded vertebrates that is structurally similar to the 2F5, and possibly 4E10, epitopes of the HIV-1 gp41 MPER.
The invention provides an HIV-1 vaccine designed to target a naïve B cell pool that can be driven to give rise to broadly neutralizing antibodies to HIV-1.